Reuse of chiral cationic Pd-phosphinooxazolidine catalysts in ionic liquids: Highly efficient catalytic asymmetric Diels-Alder reactions

Article abstract of DOI:10.1039/b611228e

Chiral cationic palladium-phosphinooxazolidine catalysts in ionic liquid afforded excellent enantioselectivity in Diels-Alder reactions and the catalyst was easily recycled eight times without any significant decrease in chemical yields or enantioselectiv

Full text of DOI:10.1039/b611228e

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Reuse of chiral cationic Pd–phosphinooxazolidine catalysts in ionic
liquids: highly efficient catalytic asymmetric Diels–Alder reactions{
Kouichi Takahashi, Hiroto Nakano* and Reiko Fujita
Received (in Cambridge, UK) 3rd August 2006, Accepted 25th September 2006
First published as an Advance Article on the web 25th October 2006
DOI: 10.1039/b611228e
Chiral cationic palladium–phosphinooxazolidine catalysts in
ionic liquid afforded excellent enantioselectivity in Diels–Alder
reactions and the catalyst was easily recycled eight times
without any significant decrease in chemical yields or enantio-
selectivity (89–99%, 88–99% ee).
efficient catalytic asymmetric DA reactions using IL as a solvent,
and with particular attention to reactions in which the catalyst can
be recovered and reused.
We here report a successful catalytic asymmetric DA reaction
1
1
using cationic Pd–phosphinooxazolidine (POZ) catalyst in IL. In
a reaction of cyclopentadiene 2 with acryloyl-1,3-oxazolidin-2-one
3a, we found that the catalyst could be reused 8 times without any
significant decrease in chemical yields or enantioselectivity (89–
99%, 88–99% ee). To the best of our knowledge, this is the first
time that a catalytic asymmetric DA reaction has been performed
repeatedly with a high level of enantioselectivity in IL.
Recently, the recovery and reuse of catalysts in a catalytic reaction
has attracted growing interest to meet the need for environmentally
friendly and cost-effective reaction processes. Many methodologies
1
have been attempted to achieve recovery and reuse; among them,
the use of immobilized chiral catalysts on soluble or insoluble
1a–c
polymers in an asymmetric synthesis is representative.
In order to compare the present results of the reaction in IL, we
first examined the DA reactions of 2 with 3a using cationic Pd–
However, these approaches require ligand or catalyst modification
for immobilization to the polymer and this modification tends to
be complicated. In addition, it is sometimes difficult to reproduce
the reaction efficiency obtained under homogeneous conditions
using a monomer catalyst. Ionic liquids have attracted extensive
interest as excellent alternatives to organic solvents, due to their
favorable properties such as non-flammability, low toxicity,
11c
POZ catalysts 1a–e (Fig. 1: new catalyst 1b and our previously
11a,b
reported catalysts 1a, c–e
) in CH Cl as a usual organic solvent
2 2
(Table 1), finding that the hexafluoroantimonate catalyst 1c was
the most effective for obtaining the highest chemical yield and
enantioselectivity (entry 4).
With these results in hand, we next examined the DA reaction of
2 with dienophile 3a in the presence of 5 mol% of superior
antimonate catalyst 1c in seven different ILs (Fig. 2), [bmim][X]
2
reusability, low cost and high thermal stability. Additionally,
they provide good solubility for a wide range of organic, inorganic
3
and organometallic compounds. To date, several reactions have
4
5a–f and [bmmim][BF ] 5g at room temperature for 48 h. Ether
been demonstrated in ionic liquid (IL). However, the use of a
catalytic asymmetric reaction has not yet been studied extensively.
Furthermore, most of the reported studies have found that the
efficient chemical yield of the reaction and the enantiomeric excess
was selected for separation, and ILs 5a–g formed a bilayer with the
ether. The desired DA adduct was isolated from the ether layer
after the purification by preparative TLC; the results are
summarized in Table 2. Moderate to good chemical yields (52–
89%) and good to excellent enantioselectivities (76–96% ee) were
obtained in the examined reactions (Table 2, entries 1–7) and both
reactivity and enantioselectivity were strongly influenced by the
(ee) obtained in usual organic solvents were difficult to reproduce
in ionic liquid, and that recycling of the catalyst was less
4
5
satisfactory. To our knowledge, only three groups have reported
a successful study which afforded satisfactory ee and recycling in
catalytic asymmetric reactions. The Diels–Alder (DA) reaction is
one of the most efficient bond-forming reactions used widely in
nature of the anions X. Using [bmim][BF ] 5a as IL, the desired
4
DA adduct 4 was obtained in 89% yield and 96% ee (Table 2,
entry 1). This result was better than those obtained in a usual
6
synthetic organic chemistry. Therefore, many research groups
organic solvent (CH
(Table 1, entry 3), and it also showed almost the same degrees as
those obtained in CH Cl at 250 uC (Table 1, entry 4). Contrary
to our expectations, [bmim][SbF ] 5c did not give a satisfactory
result (Table 2, entry 3), unlike the results obtained in CH Cl
2
2 2
Cl ) under the same reaction conditions
have reported an enantioselective version of the reaction that relies
7
on a chiral catalyst. Nevertheless, to the best of our knowledge,
2
2
only four examples of asymmetric DA reactions in IL have been
6
8
reported; these reactions used Cu–bisoxazoline, Pt–BINAP, Pt–
9
2
9
10
NUPHOS catalysts and MacMillan’s organocatalyst. Although
these reactions afforded moderate to excellent chemical yields (65–
(Table 1, entry 4). The reason for these results was clarified by
attempting reactions in 5a or 5c in the absence of catalyst 1c
100%) and good enantioselectivity (89–93% ee), they were unable
to achieve an excellent practical level of ee (over 95%) and catalysts
were successfully reused only 3 times in the experiment with the
best result. Given this background, our present aim was to explore
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku,
Sendai 981-8558, Japan. E-mail: hnakano@tohoku-pharm.ac.jp
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b611228e
Fig. 1 Pd–phosphinooxazoline complexes.
Chem. Commun., 2007, 263–265 | 263
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Table 1 Pd–POZ catalyzed asymmetric DA reaction of cyclopenta-
diene 2 with dienophile 3a in CH Cl
Table 3 Reuse of Pd–POZ catalyst 1c catalyst for asymmetric DA
reaction of 2 with 3a in IL 5a
a
2
2
Cycle
1
2
3
4
b
Yield (%)
endo/exo
ee (%)
a
89
96 : 4
96
89
97 : 3
93
90
92 : 8
85
69
92 : 8
65
c
d
DA reaction was performed in presence of catalyst 1c (5 mol%) at
room temperature for 48 h in [bmim][BF ]. Isolated yields. The
4
d
endo/exo ratio was determined by HPLC. The ee of the endo
a
c
b
c
Catalyst
Entry (mol%)
Temp. Time Yield
(uC)
ee
(%)
b
(h)
(%)
endo/exo
isomer was determined by chiral HPLC.
1
2
3
4
5
6
a
1a:BF
1b:PF
1c:SbF
1c:SbF
1d:TfO (10)
1e:ClO
4
(5)
(5)
230
245
rt
250
245
48
48
6
22
45
20
41
74
75
94
52
97
91 : 9
98 : 2
87 : 13
97 : 3
86 : 14
94 : 6
93
98
88
97
74
93
6
(5)
(5)
We next challenged the reuse of superior catalyst 1c under
optimized conditions, as shown in Table 3. The same amounts of
starting materials were again added to the separated IL layer. The
reaction produced DA adduct 4 in an 89% yield and with 93% ee
at the second run. However, enantioselectivity decreased to 85% ee
at the third run, although the chemical yield remained constant at
a 90% yield. Both the chemical yield and the enantioselectivity
decreased greatly to 69% and 65% ee, respectively, at the fourth
run. Recycling was thus carried out effectively 3 times.
6
d
d
d
6
4
(10) 245
b
Isolated yields. The endo/exo ratio was determined by HPLC.
The ee of the endo isomer was determined by chiral HPLC using a
Daicel OD-H column (0.5 mL min , hexane : 2-propanol = 90 :
c
2
1
d
11a,b
10). See references.
In order to improve the recycling efficiency of catalyst 1c, we
planned to use a mixture of [bmim][BF
solvent because IL 5a showed high viscosity at 240 uC. We again
tried to reuse catalyst 1c in [bmim][BF ]–CH Cl (1 : 2) solvent; the
4 2 2
] 5a and CH Cl as a
4
2
2
results are summarized in Table 4. Consistent with our expecta-
tions, this attempt brought about a great increase in chemical yield
with excellent enantioselectivity (99%, 95% ee, cycle 1). After the
Fig. 2 Ionic liquids.
first run, CH Cl
2
2
was removed under reduced pressure. Ether was
] 5a formed a bilayer with
Table 2 Pd–POZ 1c catalyzed asymmetric DA reaction of cyclopen-
tadiene 2 with dienophile 3a in ILs 5a–g
selected for separation and [bmim][BF
4
the ether. The desired DA adduct was isolated from the ether layer
after purification by preparative TLC. This result prompted us to
a
Yield (%)
b
c
ee (%)
Entry
Ionic liquid
endo/exo
2 2
attempt the reuse of catalyst 1c. Thus, CH Cl solvent and the same
1
2
3
4
5
6
7
5a:BF
5b:PF
5c:SbF
5d:TfO
5e:ClO
5f:Tf
4
89
61
80
52
55
77
55
20
61
96 : 4
92 : 8
95 : 5
91 : 9
92 : 8
92 : 8
92 : 8
92 : 8
90 : 10
96
85
81
76
80
83
89
—
—
amounts of starting materials were again added to the separated IL
layer. Excellent chemical yield and enantioselectivity (99%, 99% ee)
were obtained at the second run. The catalyst was successfully
recycled 7 times without any significant decrease in the excellent
enantioselectivity (94–99% ee), although the chemical yield
decreased slightly to 89%. Furthermore, the reaction afforded
fairly good results (89%, 88% ee) at the ninth run as well. The
effective number of recycling times was 8, and this was also the best
result obtained in the recycling experiment of the DA reaction in IL.
Finally, we examined the DA reaction using several dienes (2,
cyclohexadiene 6, furan 7 or 1-phenoxycarbonyl-1,2-dihydropyr-
idine 8) and dienophiles (3a–c) in a superior combination of
[bmim][BF ] and CH Cl as a solvent and superior catalyst 1c at
6
6
4
2
N
5g:BF
5a:BF
4
d
8
9
4
d
5c:SbF
6
a
b
Isolated yields. The endo/exo ratio was determined by HPLC.
c
d
The ee of the endo isomer was determined by chiral HPLC. No
Pd–POZ catalyst.
(Table 2, entries 8 and 9). Thus, ILs 5a and 5c afforded the DA
adduct in 20% and 61% yields, respectively. We assume that ILs 5c
catalyzed the reactions, with 5c showing higher catalytic activity
than 5a. This characteristic might have brought about a decrease
in enantioselectivity. Although these results prompted us to try the
reaction at a low temperature, this was not possible due to the
viscosity of the IL.
4
2
2
room temperature and at 240 uC slowly increased to room
temperature. The results are summarized in Table 5.
Unfortunately, the reactions of 2 with 3b or 3c and of
cyclohexadiene 6 with 3a did not afford results as satisfactory as
a
2 2
Table 4 Reuse of Pd–POZ catalyst 1c for asymmetric DA reaction of 2 with 3a in IL 5a–CH Cl
Cycle
1
2
3
4
5
6
7
8
9
10
Time (h)
Yield (%)
endo/exo
48
99
97 : 3
95
48
99
97 : 3
99
48
96
98 : 2
96
48
94
99 : 1
99
72
99
98 : 2
94
72
98
98 : 2
95
72
91
97 : 3
95
72
89
97 : 3
95
96
89
96 : 4
88
96
57
95 : 5
75
b
c
d
ee (%)
a
DA reaction was performed in presence of catalyst 1c (10 mol%) at 240 uC to room temperature for 48–96 h in [bmim][BF
Isolated yields. The endo/exo ratio was determined by HPLC. The ee of the endo isomer was determined by chiral HPLC.
4
]–CH
2
Cl
2
= 1 : 2.
b
c
d
2
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Table 5 Pd–POZ 1c catalyzed asymmetric DA reaction of dienes 2,
reaction, catalyst 1c was successfully reused 8 times giving 89–99%
yield and 88–99% ee. Moreover, this system was also effective in
reactions using furan 7 or 1,2-dihydropyridine 8 as dienes,
affording the corresponding DA adducts (12 and 13) at excellent
enantioselectivities. Our asymmetric DA reactions in IL have thus
been shown to be practical from both economic and environ-
mental points of view. Further studies to examine the scope and
limitations of our catalytic version of the asymmetric DA reaction
in IL are now in progress.
a
4 2 2
6–8 with dienophiles 3a–c in [bmim][BF ] 5a–CH Cl
b
Yield endo/ ee
d
Diene/
Entry dienophile Product
Temp.
(uC)
c
(%)
exo
(%)
1
2/3b
rt
2
47
40 to rt 59
90 : 10 81
90 : 10 98
Notes and references
e
e
2
2/3c
rt
2
99
40 to rt 92
85 : 15 79
85 : 15 87
1
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3
5
c) S. Brase, F. Lauterwasser and R. E. Ziegert, Adv. Synth. Catal., 2003,
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39.
3
4
6/3a
7/3a
rt
2
70
40 to rt 77
97 : 3 74
98 : 2 86
2
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Roger and K. R. Seddon, ACS Symposium Series 818, American
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f
230
46
41 : 59 12a: 85
2b: 98
1
3
4
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5
8/3a
rt
rt
19
80
—
—
23
96
g
a
b
1
DA reaction was performed in [bmim][BF = 1 : 2.
Isolated yields. The endo/exo ratio was determined by HPLC or
4
]–CH
2
Cl
2
5 (a) Y. Hamashima, H. Takano, D. Hotta and M. Sodeoka, Org. Lett.,
2003, 5, 3225; (b) N. S. Chowdari, D. B. Ramachary and C. F. Barbas
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Weinheim, 2000; (b) Cycloaddition Reactions in Organic Synthesis, ed.
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c
d
H NMR. The ee of the endo isomer was determined by chiral
e
HPLC using a Daicel OD-H column or AD-H column. The ee was
determined by comparison with the known optical rotation after
f
iodolactonization. DA reaction was performed in [bmim][BF
4
]–
g
2 2 4
CH Cl = 1 : 10. DA reaction was performed in [bmim][BF ].
7
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11a,b
group
(entries 1–3), although the enantioselectivities increased
(
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out at 240 uC to room temperature. Reactions using furan 7 or
1,2-dihydropyridine 8 as dienes were also examined (entries 4 and
5
). The obtained DA adducts 12 and 13 are valuable intermediates
12,13
in pharmacologically important compounds.
When the reac-
8
9
tion of furan 7 with 3a was carried out at 230 uC, DA adduct 12
was obtained as a 41 : 59 mixture of endo-12a/exo-12b isomers in a
1
0 J. K. Park, P. Sreekanth and B. M. Kim, Adv. Synth. Catal., 2004, 346,
9.
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4
6% yield. Although the reaction afforded the DA adducts as an
4
isomer mixture, high enantioselectivities were obtained for both
the endo-12a and exo-12b isomers; indeed, the ee of exo-12b was
almost complete (98% ee). The reaction of 1,2-dihydropyridine 8
with dienophile 3a at room temperature was unsuccessful due to
the generation of palladium black, although the reason is not clear.
The effectiveness of IL was demonstrated when IL was used alone
as a solvent, which produced DA adduct 13 in a good chemical
yield and with excellent enantioselectivity (80%, 96% ee).
1
12 (a) P. Vogel, D. Fattori, F. Gasparini and C. Le Drian, Synlett, 1990,
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In summary, we have developed a highly efficient asymmetric
DA reaction using cationic Pd–POZ catalyst in IL. The
7582.
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8299.
ion and [bmim][BF ] 5a as an IL was found to be effective in the
4
reaction of 2 with 3a, affording the corresponding DA adduct 4.
Additionally, the chemical and optical yields were high using a
mixture of [bmim][BF ] 5a and CH Cl as a solvent. In the
4
2
2
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Chem. Commun., 2007, 263–265 | 265